A Platform for Large-scale Discovery in Common Disease: Project Summary A comprehensive understanding of the genome architecture variants underlying inherited human disease phenotypes and protective alleles will facilitate improved diagnosis, prognosis, disease management, and the development of new treatments for hundreds of millions of people worldwide. In support of this goal, we propose to apply our established, state-of-the-art DNA sequencing and analysis platform to comprehensively identify rare variation influencing susceptibility to common complex diseases corresponding to three disease themes: 1) cardiovascular disease and metabolic risk, 2) autoimmune disease including Type 1 diabetes and rheumatoid arthritis, and 3) developmental and degenerative diseases including cleft lip/palate, idiopathic scoliosis and macular degeneration. Where possible, we will leverage emerging methods and technology to advance the state of the field and achieve our program goals. Our approach extends the discovery power of low-cost whole genome sequencing (WGS) with innovative laboratory and computational techniques to comprehensively interrogate the full spectrum of human genome variation. We developed these studies with substantial input from expert collaborators whose continued involvement and disease-specific expertise will be critical for success. Ultimately, the diversity of our proposed projects - in ters of disease phenotypes, sample ancestries, and study designs - will provide a better understanding of the genetic architecture of common disease and the extent to which it is shared across world populations.